A health need exits for a dosage form comprising the therapeutically active drug of the general formula (1): in either exo or endo form, the base, and pharmaceutically acceptable salts thereof: ##STR3## especially for a dosage form that exhibits an essentially zero order release rate of the drug over a long period of time. In formula (1), A is a member selected from the group consisting of an oxygen atom, a methylene group and an ethylene group, the full line embracing a broken line (-- -- --) designates either a single bond or a double bond, R is a phenyl group optionally substituted with a member selected from the group consisting of halogen, an alkyl group of 1 to 4 carbons, an alkoxy group of 1 to 4 carbons, a trifluoromethyl group, a 2-pyridyl group and a 2-pyrimidinyl group, and wherein n is an integer of 3 or 4.
A presently preferred drug embraced by formula (1) is represented by formula (2). ##STR4## The drug depicted by formula (2) is known also as tandospirone, or by the name 4,7-methano-1H-isoindole-1,3(2H)-dione, hexahydro-24--(2-pyrimidinyl)-1-piperazinyl!butyl!-(3a.alpha.,4.beta.,7. beta.,7a.alpha.)-2-hydroxy-1,2,3-propanetricarboxylate (1:1) or as N-4-4-(2-pyrimidinyl)-1-piperazinyl!butyl-2,3-norbornanedicarboximide; and the base and pharmaceutically acceptable salts thereof. The drugs of both formulae are taught in prior art patents U.S. Pat. Nos. 4,507,303; 4,543,355; 4,598,078 and 5,011,841. The beneficial drugs of the formulae are administered by the prior art in rapid release manufactures, such as tablet, capsule, syrup and suspension. With such rapid release manufactures, the drug is administered by repeated administration to produce a therapeutic level.
Generally, for rapid release manufactures, as known to the prior art also as instant release dosage forms, the release rate profile follows the cube root law, that is, the release rate decreases with time, Inter. J. Pharm., Vol. 62, pp 143-151, 1990. This release rate pattern provides unpredictable therapy and it is often accompanied by a period of time, when the patient is not receiving the drug. A critical health need exists for a controlled-release dosage form that overcomes the shortcomings known to the prior art. A controlled-release dosage form provides drug continuously to the patient for constant therapy for better health. A dosage form made with controlled-release drug delivery properties, provides drug at a controlled rate as a zero order plot of the rate of release of drug versus time shows an essentially straight line that indicates the rate of release is independent of time. A dosage form, according to the present invention, that provides for the controlled-rate of administration of drugs of formulae of (1) and (2), would represent a major advancement to the drug delivery art, because the controlled and extended zero order release of drug in a known and uniform dose over a long period of time reinforces better therapy.
In light of the above presentation, it will be evident to those versed in the dispensing art, that a pressing need exists for a dosage form possessing a zero order controlled rate of release that can deliver the valuable drug of formulae 1 and 2 for its therapy. The pressing need exists for a dosage form having a zero order controlled-rate of release, which controlled-rate is generated by osmotic diffusion, bioerosion, or ion-exchange activity, while simultaneously maintaining the physical and chemical integrity of the dosage form during the drug delivery period.